The present invention relates to pharmaceutical compositions which comprise a core and a drug emulsion layer, and, optionally, a protective layer. The preferred core is a round, spherical core which comprises sucrose, lactose, starch, talc, or microcrystalline cellulose or any combination thereof. The preferred drug is an azole antifungal or antibacterial drug. Examples of the azole antifungal or antibacterial drug include, but are not limited to, itraconazole, saperconazole, ketoconazole, and fluconazole. The drug emulsion layer includes the drug, an emulsifier, a binder, and an absorbent aid. The preferred emulsifier is vitamin E polyethylene glycol succinate. The preferred binder is hydroxypropyl methylcellulose. The preferred absorbent aid is DL malic acid. The azole antifungal or antibacterial drug is preferably dissolved in organic solvents, such as ethanol and methylene chloride. The protective layer contains polyethylene glycol (PEG) 20,000 and is coated on the emulsified layer. The present invention also relates to a method for making the pharmaceutical preparation and methods of using the pharmaceutical preparation to treat patients with fungal or bacterial infections.
U.S. Pat. No. 4,267,179 discloses a number of 1H-imidazole and 1H-1,2,4-triazole derivatives having antifungal and antibacterial properties. Specifically, a number of heterocyclic derivatives of (4-phenyl-1-piperazinyl-aryloxymethyl-1,3-dioxolan-2-yl) methyl-1H-imidazoles and 1H-1,2,4-triazoles are described. Among these azole compounds and their derivatives, itraconazole, saperconazole, ketoconazole, and fluconazole are currently commercially available. These commercially available azole compounds are known for their broad spectrum of antimicrobial activity. For example, they are found to be highly active against a wide variety of fungi such as Microsporum canis, Pityrosporum ovale, Ctenomyces mentagrophytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Aspergillus fumigatus, Sporotricum schenckii and Saprolegnia species. They are also active against bacteria, such as Erysipelotrix insidiosa, Staphylococcus hemolyticus and Streptococcus pyogenes. 
Itraconazole is currently commercially available under the trade name Sporanox(copyright) in capsule or tablet form from Janssen Pharmaceutica (Beerse, BE). The chemical structure of itraconazole is disclosed in U.S. Pat. No. 4,267,179 as (xc2x1)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, having the formula of: 
Itraconazole is especially known for its activity against a broad range of fungal inductions such as those caused by Trichophyton rubrum, Tricophyton mentagrophytes, Epidermophyton floccsum and Candida albicans. 
The chemical structure of saperconazole is disclosed in U.S. Pat. No. 4,916,134 as (xc2x1)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one. Saperconazole has antimicrobial activity, in particular against fungi belonging to the genus Aspergillus.
Ketoconazole was the first of the azole antifungal agents to become commercially available. The chemical structure of ketoconazole is disclosed in U.S. Pat. No. 4,144,346 as cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-dioxoolan-4-yl]methoxy]phenyl]piperazine. Ketoconazole is an orally active, broad-spectrum antifungal agent. The compound, an imidazole derivative structurally related to miconazole and clotrimazole, impairs the synthesis of ergosterol, which is the principal sterol of fungal cell membranes.
Fluconazole is a water-soluble triazole with greater than 90% bioavailability after oral administration. The chemical structure of fluconazole is disclosed in U.S. Pat. No. 4,404,216 as 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol. Fluconazole is used extensively to treat a wide range of Candida infections. In particular, it is widely used in connection with therapy for oropharyngeal candidiasis in patients with advanced HIV infection and AIDS.
The solubility and bioavailability of itraconazole and saperconazole are low due to the fact that these compounds have a low solubility in water and a low pKa value. For example, the solubility of itraconazole is less than 1 xcexcg/ml in water and the pKa value of itraconazole is 3.7.
There have been several reports which show improvement of solubility and bioavailability of itraconzole and/or saperconazole. For example, U.S. Pat. No. 6,100,285 describes a solvent system for dissolving itraconazole. The solvent system contains volatile organic acid solvents such as acetic acid and formic acid, with the solvent itself in an aqueous solution of the acid.
U.S. Pat. No. 5,707,975 discloses a pharmaceutical formulation for itraconazole and saperconazole which is said to have improved solubility and bioavailability. The formulation uses cyclodextrins or the derivatives of cyclodextrins (e.g., hydroxypropyl-xcex2-cyclodextrin) as a solubilizer; an aqueous acidic medium as a bulk liquid carrier (such as hydrochloric acid to achieve optimum pH of 2.0xc2x10.1); and an alcoholic co-solvent (e.g., PEG 400) to dissolve the compounds.
U.S. Pat. No. 5,633,015 discloses a pharmaceutical formulation for itraconazole and saperconazole in the form of beads. The beads comprise a central, rounded or spherical core, a coating film, and a seal-coating polymer layer. The core has a diameter of about 600 to about 700 xcexcm (25-30 mesh). The coating film contains a hydrophilic polymer (such as hydroxypropyl methylcellulose) and a drug (e.g., itraconazole and/or saperconazole). The seal-coating polymer layer is applied to the drug coated cores to prevent sticking of the beads, which would have the undesirable effect of a concomitant decrease of the dissolution rate and of bioavailability. The beads use polyethylene glycol (PEG), in particular, PEG 20,000, as the seal-coating polymer.
U.S. Pat. No. 6,039,981 discloses a pharmaceutical composition which comprises a fused mixture of itraconazole and phosphoric acid, a pharmaceutically acceptable carrier, and a surfactant. The fused mixture of itraconazole and phosphoric acid is prepared by heating the mixture to a temperature ranging from 100 to 170xc2x0 C. to obtain a homogeneous melt mixture.
The present invention provides novel pharmaceutical compositions for an azole antifungal or antibacterial drug which comprise a core and a drug emulsion layer. The drug emulsion layer comprises the azole antifungal or antibacterial drug, an emulsifier, a binder, and an absorbent aid. The present pharmaceutical compositions are distinctively different from that of U.S. Pat. No. 5,707,975 because no cyclodextrin or its derivative is used as a solubilizer. The present pharmaceutical compositions are also different from that of U.S. Pat. No. 5,633,015 because it contains an absorbent aid in the drug emulsion layer. Furthermore, the present pharmaceutical compositions are distinctively different from that of U.S. Pat. No. 6,039,981 because no fusion of itraconazole with phosphoric acid is used.
The present pharmaceutical compositions display similar and/or superior solubility and bioavailability as compared to the commercially available azole antifungal or antibacterial drugs.
The present invention provides two orally administered pharmaceutical preparations in the form of pellets, which can be further encapsulated. The first pharmaceutical preparation comprises a core coated with a drug emulsion layer. Optionally, a protective layer which contains polyethylene glycol (PEG) 20,000 is coated onto the emulsion layer. The core is rounded or spherical in shape, which can be obtained from a bulk drug manufacturer or produced in-house. Examples of the core materials include, but are not limited to, sucrose, lactose, starch, talc, or microcrystalline cellulose or a combination thereof. Optionally, polyvinyl pyrrolidone (PVP K-30) can be used as a plasticizer in combination with the core materials. The drug emulsion layer comprises an azole antifungal or antibacterial drug, an emulsifier, a binder, and an absorbent aid. Examples of the azole antifungal or antibacterial drug include, but are not limited to, itraconazole, saperconazole, ketoconazole, and fluconazole. The preferred weight ratio between the core and the drug is 1:0.2-0.6. Examples of the emulsifier include, but are not limited to, polyoxypropylene-polyoxyethylene block copolymers (e.g., Poloxamer 188), polyethylene-sorbitan-fatty acid esters (e.g., Tween 80), sodium lauryl sulfate, and vitamin E polyethylene glycol succinate. The preferred emulsifier is vitamin E polyethylene glycol succinate. Examples of the binder include, but are not limited to, polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and methylcellulose (MC). The preferred binder is HPMC. Examples of the absorbent aid include, but are not limited to, DL-malic acid, citric acid, ascorbic acid, and alginic acid. The preferred absorbent aid is DL-malic acid. The drug is preferably dissolved in organic solvents. Examples of the organic solvents include, but are not limited to, methylene chloride, ethanol, and isopropanol. The preferred organic solvents are a combination use of methylene chloride and ethanol.
The method for making the first pharmaceutical preparation comprises the steps of: (a) obtaining a core; (b) mixing an emulsifier with a binder to form an emulsion; (c) dissolving an azole antifungal or antibacterial drug in organic solvent, followed by mixing the dissolved drug with the emulsion of (b); and (d) spraying (c) onto the core of (a). The protective layer is prepared by dissolving PEG 20,000 in methylene chloride and ethanol, preferably at a ratio of about 1:1-1.1, v/v.
The core of the pharmaceutical preparation is commercially available. Alternatively, it can be produced as follows: (a) dissolving polyvinyl pyrrolidone in isopropanol to produce a binder solution; and (b) spraying the binder solution of (a) onto sucrose particles to form the core. It is recommended that starch and talc be added to the sucrose core at the same time as the binder solution of (a) is sprayed onto the sucrose particles.
The first pharmaceutical preparation can be used for treating patients with a fungal or bacterial infection.
The present invention also provides a second pharmaceutical preparation which comprises: (a) a core; and (b) a coating containing an effective amount of an azole antifungal or antibacterial drug, vitamin E polyethylene glycol succinate as an emulsifier, hydroxypropyl methylcellulose (HPMC) as a binder (which can be replaced with polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), or methylcellulose (MC)), and DL-malic acid as an absorbent aid. Optionally, a protective layer can be added on top of the drug coating. The core and the drug are composed of similar or the same materials as those described in the first pharmaceutical preparation. The preferred weight percentage of vitamin E polyethylene glycol succinate is about 0.005-5%, most favorably 0.01-0.2% by weight of the total pharmaceutical preparation. The preferred weight percentage of DL-malic acid is about 0.005-6%, most favorably 0.01-0.02% of the total pharmaceutical preparation. The azole antifungal or antibacterial drug is preferably dissolved in methylene chloride and ethanol. The preferred volume ratio of methylene chloride and ethanol is about 1:1-1.1, v/v.
The method for making the second pharmaceutical preparation comprises the steps of: (a) obtaining a core; (b) dissolving the vitamin E polyethylene glycol succinate with ethanol; (c) adding the HPMC to (b); (d) adding the azole antifungal drug to (c); (e) adding methylene chloride to (d) to form a drug emulsion; and (f) spraying the drug emulsion of (e) onto the core of (a). Optionally, a protective layer can be sprayed onto the emulsion layer. The protective layer contains PEG 20,000, which is dissolved in methylene chloride and ethanol. The method for preparing the core is similar to or the same as that described in the first pharmaceutical preparation.
The second pharmaceutical preparation can also be used in treating patients with fungal or bacterial infection.